Dosage forms having prolonged active ingredient release

ABSTRACT

A pharmaceutical unit dosage form comprising a therapeutically effective dose of a 4-phenylbutyric acid salt having prolonged release of the active ingredient, being suitable for alleviating and curing various diseases upon once or twice daily oral administration, a method of preparation of said pharmaceutical formulation and the use thereof for the treatment of benign prostate hyperplasy, cancer, leukemias, cystic fibrosis, AIDS, kidney and liver diseases, thalassemia and urea cycle disorders comprising the twice-daily oral administration of a therapeutically effective dosage thereof to a patient.

FIELD OF THE INVENTION

[0001] The invention relates to solid, orally administrablepharmaceutical dosage forms having prolonged active ingredient releasefor once or twice daily administration, containing a 4-phenylbutyricacid salt as active ingredient, to methods for producing them and theiruse for treating various diseases, known to be beneficially influencedby the active ingredient.

BACKGROUND OF THE INVENTION

[0002] The 4-phenylbutyric acid sodium salt (sodium 4-phenylbutyrate)and its use for the treatment of a variety of illnesses, such as benignprostate hyperplasy, cancer, cystic fibrosis; HIV, kidney and liverfailures, thalasemia and urea cycle disorders are known. For example, WO85/04805 (Brusilow) discloses a process for waste nitrogen removal Inhuman beings, wherein 4-phenylbutyrate is administered. DE 19,810,383(Manhart, et. al.) describes 4-phenylbutyrate as apoptosis inducingagent for neoplastic therapy. WO 9937150 (Pandolfi et al.) decribes atranscription therapy for cancers using a retinoic acid and/or aninhibitor of histone deacetylase. WO 93/07866, WO 9510271 or EP 725635(Samid) disclose compositions and methods using phenylacetic acidderivatives for therapy and prevention of a number of pathologies,Including cancer, AIDS, anemia, and severe beta-chainhemoglobinopathies, which emerged in a number of U.S. patents. WO9856370 (U.S. Pat. No. 6,207,195, Walsh et.) describes therapeuticsodium 4-phenylbutyrate containing nanospheres for treatment of cysticfibrosis by CFTR gene therapy. WO 9840078 (Rephaeli) disclosestherapeutic augmentation of oxyalkylene diesters and butyric acidderivatives with inhibitors of fatty acid beta-oxidation.

[0003] 4-Phenylbutyric acid is rather quickly broken down in the humanbody by beta-oxidation to phenylacetic acid. This acid eliminatesglutamine from cells, which is essential for the growth of cancer. Adeficiency of glutamine in cancer cells results in apoptosis. In orderto counteract the fast elimination of 4-phenylbutyrate from the body,about 10 to 40 g per patient and day are administered. In order toattain and maintain constant levels of the active ingredient in theplasma also infusion solutions are used. These, however, are unsuitablefor ambulant treatment. The use of large amounts of 4-phenylbutyrate isalso a commercial problem. The active compound is very expensive and hasto be taken for several months up to years.

[0004] Accordingly, it would be desirable to have a 4-phenylbutyrateformulation that avoids the problems associated with application oflarge amounts of this compound. The formulation should be effective withlower amounts of the active ingredient. On repeated administrationconstant therapeutically effective plasma levels should be provided;exhibiting a minimum of fluctuations between the maximum and minimumconcentrations of active Ingredient in the blood. A possible method ofreducing the influx time of the active ingredient and of minimisingfluctuations may be achieved by controlling the dissolution of theactive ingredient over a longer period of time than is the case withconventional formulations. A solution to this problem is offered by thetherapeutic system OROS® (F. Theeuwes, J. Pharm. Sci., Vol. 64,12,1987-1991, 1975). A disadvantage of the OROS systems is that they aretechnically difficult to produce.

[0005] A formulation would be desirable with a slow release rateproviding low plasma level fluctuations, which remain constant over arelatively long period. Slow release formulations or retard formulationsare known in the pharmaceutical art. However, they cannot simply be usedfor particular problems, but have to be individually designed for eachactive ingredient and for each indication. This requires some inventiveingenuity.

[0006] The release rate of the active ingredient from tablets or powdersis influenced by the solubility characteristics of the activeingredient, which, in turn, depend upon solubility, particle size,specific surface area and interactions with other excipients.Dissolution may be retarded by means of diffusion barriers in the coreof the tablet or in a film coating. Retarding dissolution by means ofdiffusion barriers in the core is a principle that is frequently used onaccount of its technical simplicity. It is possible to use variousexcipients, for example swelling agents, lipophilic substances oralternatively plastics, as diffusion barriers. The matrix, that is tosay the homogeneous substance composition, can be such that the releaseof the active ingredient takes place by diffusion of the dissolvedactive ingredient, especially through the water-filled pores in thetablet core and if required in special cases by diffusion through theretarding substance which must for that purpose be in a suitablestructural form. Alternatively the matrix also can be in a form that issubjected to slow erosion and in this way effects delayed release of theactive ingredient.

[0007] In all those cases the diffusion path and the active diffusionsurface for the release change with time. For that reason it is clearthat with matrix systems neither in vivo nor in vitro is it usuallypossible to expect any release having linear kinetics, that is to say ofthe 0^(th) order. Instead, the release is generally a function of theroot of the time (Square root dissolution; Higuchi; J. Pharm. Sci. 52,12, 1963, 1145). The validity of the Higuchi law for the hydrocolloidmatrix has also been documented in numerous publications (Ford et al.,Int. J. Pharm., 24, 1985, 327-338; 339-350; 1985).

[0008] Therapeutic dosage forms in which the medicinal substance isincorporated into a soluble or erodible matrix would be desirable onaccount of the ease of their manufacture, the low degree of variationbetween different manufacturing processes and because of the relativelylow costs.

[0009] The use of hydrophilic gums, such ashydroxypropylmethyl-cellulose, as delaying matrix material is known andhas been tested with a large number of active ingredients. Noformulation has been disclosed hitherto that would be suitable forattaining the desired objectives with 4-phenylbutyrates.

[0010] The behaviour of a specific medicinal substance when combinedwith a retarding excipient cannot be calculated or generally predicted.Although the basic factors affecting release from matrix systems havebeen well researched, interactions between the retarding material on theone hand and the active ingredient and other excipients on the other canaffect the retarding action in various ways.

[0011] The question of release kinetics is a multi-factored problem.Responsible factors are, in addition to the dissolution properties ofthe active ingredient, the rate of water absorption and thus the rate ofswelling of the Interface to be penetrated, the diffusion co-efficientof the substance through the swollen mass and also the time-dependentthickness thereof. It can clearly be imagined that release of the 0^(th)order is brought about by the existence of an equilibrium between theerosion of the tablet and the dissolution properties of the activeingredient, so that the diffusion paths for the substance remainconstant during the dissolution time.

[0012] However, it is important to realise that it is impossible topredict, whether the release rate will be of the the 0^(th) or any otherorder. From the large number of known pharmaceutical excipients it isnecessary to select those suitable for the desired purpose and to,process them in suitable quantity ratios, which must likewise beselected, to form an effective matrix system.

PROBLEM OF THE INVENTION

[0013] The problem underlying: the present invention was to overcome theexisting drawbacks of using 4-phenylbutyrate salts in alleviating andcuring a variety of diseases. As the substance and its beneficialhealing capacity was known for a long time there must have beenprejudices for developing a solid, orally administrable pharmaceuticaldosage form that is technically easy and cheaply to produce and whichexerts its therapeutic effects upon oral once or twice daily applicationin lower than usual amounts.

[0014] A pharmaceutical dosage form, which fulfils the requirements ofreducing the dosage without reducing the therapeutic activity, which canbe more easily and more cheaply produced, and which can be more easilyapplied also during prolonged ambulant treatment, is quite often a luckystrike. The treatment of patients, and the surprising success achievedtherewith can be used as a measure for inventive step.

[0015] Such surprising dosage form is provided by the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The invention relates to a pharmaceutical unit dosage formcomprising a therapeutically effective amount of a. 4-phenylbutyric acidsalt, having prolonged release of the active ingredient, and beingsuitable for alleviating and curing various diseases of a human patientupon once or twice daily oral administration to said patient.

[0017] Pharmaceutical unit dosage forms are especially tablets andpowders introduced into capsules, for example hard gelatine capsules.

[0018] Salts of 4-phenylbutyric acid may be of the alkaline or earthalkaline type, e.g. lithium, sodium, potassium, magnesium or calcium.Preferred is the sodium salt. The unit dosage form contains-about 50 to1000-mg, preferably about 100 to 500 mg, most preferably about 250 mg ofthe active compound.

[0019] By prolonged release of the active ingredient is to be understoodespecially a rate of release of the active ingredient during a period ofabout 6 to 12 or up to 24 hours.

[0020] The prolonged release dosage form or retard form is a homogeneousmatrix in powder or preferably in tablet form comprising about 20-80%,preferably about 35% by weight of a 4-phenylbutyric acid salt.

[0021] The term “about” as used hereinbefore and hereinafter inconnection with weights or other measures should indicate a possibleaberration of between +/−5 to 10%.

[0022] The matrix is provided by about 5-50%, preferably about 20% byweight of hydroxypropylmethylcellulose having a molecular weight in therange of about 20,000-250,000, and, in dependence upon the nature of theretardation of release desired, 2-25% by weight of excipientscontrolling release and optionally other pharmaceutically acceptableexcipients making up the weight of the dosage form to 100%.

[0023] A therapeutically effective amount is the amount required formaintaining the desired therapeutic effect, in particular of inhibitingglutamate metabolism, over a period of about 24 hours. Thetherapeutically effective amount of the hitherto known dosage forms is10,000 to 40,000 mg per, day. In the present invention the effectivedaily amount is significantly reduced. One dosage unit form containsfrom about 20 to 9000 mg of the 4-phenylbutyrate, preferably about 250mg. The effective dose upon twice daily administration amounts to merely40 to 2,000 mg, preferably 500 mg per day.

[0024] A matrix is defined in galenical pharmacy as being a well mixed,homogeneous substance composition that can be compressed to form tabletsor can be introduced in the form of a powder into capsules, preferablyhard gelatine capsules.

[0025] The tablets or capsules contain, for example, 100-500 mg,preferably 250 mg, of active ingredient, for example sodium4-phenylbutyrate.

[0026] The release controlling pharmaceutically acceptable excipientsare lipophilic or hydrophilic substances (release retarders, liberationcontrollers) that modify the swelling process of the retarding matrix.

[0027] Hydrophilic release retarders are solid polyethylene glycols, forexample polyethylene glycol 4,000 or 6,000, or polyvinyl-pyrrolidones,for example Kollidone 25®, Kollidone 30® or Kotlidone 90® (brand namesof BASF GmbH) with various viscosities, and also vinylpyrrolidone/vinylacetate copolymers, for example Kollidone VA 64® (brand name BASF GmbH).

[0028] Lipophilic release retarders are pharmaceutically acceptablederivatives of vegetable fats in solid tablet form with a melting pointof above 600, such as vegetable fatty acids with chain lengths of atleast 16 carbon atoms, for example stearic acid C16, palmitic acid C18or mixtures thereof, and especially vegetable oils hardened byhydrogenation, for example hydrogenated castor oil, such as Cutina HR®(brand name of Henkel) or hydrogenated cottonseed oil, such as Emvelop®or Lubritab® (brandnames of Mendell). For the preparation of tablets thelipophilic release retarders must be suitable for tabletting. About2-25% release retarder are used, based on the final weight of the tabletor capsule.

[0029] The hydroxypropylmethylcellulose (HPMC) preferably used accordingto the invention and representing the retarding principle, is of the2208 USP XXII type, has a molecular weight of 20,000-250,000, preferably20,000-120,000, and has a preferred viscosity of 100-15,000 cps.Especially suitable are Methocel K® types which produce the fastestswelling, for example Methocel K100M Premiums (Prochem Chemical Co.),Methocel KIOLV®, Methocel K4M® and Methocel K15M® (brand names, DOWCHEMICAL CO.) or the virtually equivalent Metolose 90SH® types, forexample Metolose 90SH100®, Metolose 90SH4,000® and Metolose 90SH15,000®(brand names, Shin-Etsu Chemical Co. Ltd.). Approximately 5-50% byweight, preferably 10-40% by weight, HPMC are used, based on the finalweight of the tablet or capsule filling.

[0030] Further excipients are certain fillers, lubricants andflow-regulating agents, which may likewise exert an effect, albeit asmall one, on the release kinetics.

[0031] Fillers are corn starch, lactose, microcrystalline cellulose,mannitol or dicalcium phosphate, and also mixtures thereof. Useful isfor example a mixture of 75% lactose and 25% mnicrocrystallinecellulose, for example Cellactose® (brand name of Meggle GmbH). Thefillers must be carefully selected in suitable amounts and matchedexactly to specific formulation. In addition, attention should be paidto the compression properties. They are used in an amount making up theweight of the tablet to 100%;

[0032] Lubricants are, for example, magnesium stearate, stearic acid ofa suitable quality, calcium stearate, and mixtures thereof, magnesiumstearate being preferred, and are preferably used in an amount of0.1-1%, based on the final weight of the formulation.

[0033] Suitable agents that act on the flowability of the powder to beencapsulated or compressed (flow-regulating agents) are, for example,highly dispersed silicon dioxide, preferably in an amount of 0.25-1%,based on the final weight of the formulation.

[0034] The tablets can be provided with a neutral film coating or with afilm coating that delays the release of the active ingredient, that isto say that produces a lag time. A stomach resistant film coating ispreferred.

[0035] A film coating having no retarding action consists, for example,of film-formers, pigments, anti-adhesive agents and plasticisers. Such afilm former may consist of fast-dissolving constituents. In this case itis preferable to use low-viscosity hydroxypropylmethylcellulose type2910 USP XXII, for example Methocele E5 or E 15 (Dow Chemicals Ltd.) orPharmacoaet 606 (Shin-Etsu).

[0036] A film coating having retarding action may consist ofwater-insoluble but water-permeable polymers which, as a diffusionbarrier, not only bring about a lag time at the beginning but alsoaffect the swelling behaviour of the core over a prolonged period as aresult of the initially altered water permeation. Preferredwater-insoluble polymers are water-insoluble derivatives of methacrylicacid, for example methyl/ethyl acrylate, such as Eudraget® RS or RL andEudragit® NE (brand names, Rohm Pharma GmbH) and mixtures thereof.

[0037] The film coating may also contain excipients customary infilm-coating procedures, such as light-protective pigments, for exampleiron oxide, in an amount of about 40-80%, or titanium dioxide, in anamount of about 100-150%, anti-adhesive agents, for example talc, in anamount of about 50-200%, and also suitable plasticisers, matched to thepolymer, of the polyethylene glycol series, for example PEG 400 or PEG6,000, or triethyl citrate in the case of films based on methacrylicacid derivatives, such as Eudragit® RSIRL and NE, in an amount of about30-60% (percentages are in each case based on the dry coatingsubstance). When aqueous dispersions of the said Eudragit® types areused, then, for example, Tween 80 is necessary as aggregation inhibitor.

[0038] For the preparation of the powder components for filling hardgelatine capsules it is possible to use the same powder components asthose used for the preparation of tablets. The release kinetics intablets are also dependent upon geometric factors, such as the shape andsize of the tablets. Biconvex tablets having a diameter of approximately5-11 mm, especially 7-9 mm, and a thickness of 3-10 mm, especially 6.8mm, are preferred.

[0039] A preferred tablet contains, for example:

[0040] about 250 mg of sodium phenylbutyrate,

[0041] about 146 mg of hydroxypropylmethylcellulose type 2208 USP XXIIof 100 or 4000 cps,

[0042] about 261 mg of lactose,

[0043] about 30 to 60 mg, in particular 31.25 mg, of microcrystallinecellulose (Avicel® PH 102, Select chemie, or Cellactose®, Meggle),

[0044] about 10 mg of hardened vegetable oil, or e.g. talcum,

[0045] about 1.5 mg of magnesium stearate, and

[0046] optionally about 1 mg of highly dispersed silicon dioxide,

[0047] so that cores prepared thereof weigh about 0.7 g.

[0048] Advantageously, a number of 24,000 of the cores are provided witha film coating for example by using a colloidal dispersion containingabout 7,850 g of isopropylalcohol, about 3'360 g of Eudragit®L 12.5,about 66 g of dibutyl phthalat, about 18.0 g of Miglyol® 812 and about56 g of polyethylenglycol PEG 400.

[0049] For tablets containing 100 and 500 mg of active ingredient,corresponding aliquots of the excipients should be used.

[0050] Preferred pharmaceutical dosage forms contain 250 mg of sodium4-phenylbutyrate, and are specifically the tablets described in Example1.

[0051] In a further embodiment the invention relates also to a processfor the preparation of a pharmaceutical dosage form according to theabove description, characterised in that the dosage form is prepared ina conventional manner.

[0052] The constituents of the tablet cores are, if necessary, ground tothe desired particle size, mixed homogeneously with one another at thesame time or in a specific sequence and, optionally, granulated bymoistening with water, dispersing and drying the granular mass. If themixture is granulated, the fillers, flow agents and lubricants can beadded to the granules after granulation. The mixture of the coreconstituents is compressed to form tablets having a hardness ofapproximately 50-100 N, preferably 90 N, or may be introduced as suchinto hard gelatine capsules.

[0053] The film-coating is effected in a conventional manner by mixingthe constituents of the film coating with water, coating the compressedtablet cores therewith and drying at approximately from 30 to 40° C.,preferably approximately 35° C.

[0054] In a further embodiment the invention relates to the use of apharmaceutical dosage form in accordance with the present invention forthe treatment of diseases that can be influenced by said dosage form,comprising the once or twice daily oral administration of apharmaceutical dosage form according to the present invention to apatient in need thereof and to be treated.

[0055] Depending upon the age and weight of the patient, the nature andseverity of the illness, as well as the general condition of thepatient, and also on the salt of the 4-phenylbutyric acid to beadministered, the dosage forms used contain about 100 to about 1,000 mg,preferably 250 mg of active ingredient.

[0056] Diseases that can be beneficially influenced by the presentdosage form include in particular benign prostate hyperplasy, cancer,leukemias, cystic fibrosis, AIDS, kidney and liver diseases, thalassemiaand urea cycle disorders. For example, the treatment of anadenocarcinoma of the prostate can be carried out by administering twicedaily, e.g. in the morning and evening, a pharmaceutical tabletformulation containing 250 mg of sodium 4-phenylbutyrate. Thetherapeutic effect is evident after treatment of about one month whenthe pains disappear. Treatment may be continued for several month oryears until a satisfactory effect is observed or the patient is totalfree of the disease. The 4-phenylbutyrate exerts no side effects evenover a long period of treatment.

[0057] The following Examples illustrate the invention but do notconstitute a limitation thereof.

EXAMPLE 1 Production of Slow Release Tablet with 250 mg of Sodium4-Phenylbutyrate

[0058] A mixture of 6,000.0 g of sodium 4-phenylbutyrate from TripleCrown America, Inc., 6,280.0 g of lactosum monohydricum 3,500.0 g ofMethocel K100 M Premium (Prochem), and 750.0 g of Avicel PH 102 (SelectChemie) is wettened with 4,000.0 g of aqua purificata (water purified byinversion osmosis) and dried in cold air during 18 hours. The mixture isforced through a sieve IV mm and dried again during 10 hours with air of40° C. A mixture of 240.0 g of talcum and 30.0 g of magnesium stearateis admixed during 20 minutes and the mixture is pressed into tablets of0.70 g each, a thickness of about 6.8 mm and with a hardness of 90Newton. Yield: 24,000 tablet cores.

[0059] The mixing is carried out with a Diosna Mixer, the drying in aLükon drying cabinet, the sieving with a Köhler & Bosshard sievingmachine, and the tablet pressing with a Korsch tablet press EK II.

[0060] The cores are provided with a film coating for example by using acolloidal dispersion containing 7,850 g of isopropylalcohol, 3,360 g ofEudragit L 12.5, 66 g of dibutyl phthalat, 18.0 g of Miglyol 812, and 56g of polyethylenglycol PEG 400. The suspension is sprayed at 3.5 atO and25° C. onto the 24,000 cores. The film-coated tablets are dried in acirculating air drying cabinet for at least 4 hours at 35° C.

EXAMPLE 2 Human Test Results

[0061] Following are descriptions of treatments and test resultsobtained from human

Example 2 Human Test Results

[0062] Following are descriptions of treatments and test resultsobtained from human patients.

[0063] Patent Nr. 1, MM, Born Feb. 5, 1909:

[0064] This patient presented on Apr. 24, 1995 with a cancer of theprostate with a prostate specific antigen (PSA) of 36 μg/l and withpositive prostate biopsies, revealing adenocarcinoma of the prostate.The positive bone scan revealed multiple bone metastasis with lumbar andthoracic spine, ribs and pelvis. Because of progressive bone pains heunderwent bilateral orchiectomy in February 1996. He became free of painuntil November 1998 when he again suffered bone pains mainly in hisback. He was than treated orally twice daily with 250 mg of sodiumphenylbutyrate retard tablets according to Example 1. Four weeks laterhe was free of pain. He stayed on this medication until June 2001without any other symptoms of the prostate carcinoma. The PSA and thealkaline phosphatase were always within normal limits. No side effectsattributable to the treatment have been observed.

[0065] A work-up in June 2002 revealed no symptoms of signs of an activeprostate carcinoma. He stays now in complete unmaintained remission for12 months.

[0066] Patient Nr. 2, KR, Born Jul. 24, 1919:

[0067] This patient presented in March 1997 with a pathological fractureof the 8^(th) thoracic vertebra caused by metastatic distruction. Themultiple biopsies of the slightly enlarged prostate was positive foradenocarcinoma on both sides. The bone scan showed multiple uptake inribs and vertebrates. On Apr. 10, 1997 he underwent bilateralorchidectomy. From May 1997 until September 2000 he was treated orallytwice daily with 250 mg of sodium 4-phenylbutyrate retard tabletsaccording to Example 1. The last control in August 2001 revealed nosymptoms. The bone scan showed no pathological uptakes. The4-phenylbutyrate was well tolerated without side-effects.

[0068] After 20 months in ummaintained remission he died from asecondary disease. His post mortem examination revealed histological notumor tissue in the prostate or elsewhere.

[0069] Patient Nr. 3, M.W., Born Mar. 11, 1911:

[0070] In October 1997 a biopsy of the prostate due to elevated PSA(17.5 μg/l) revealed a cancer of the prostate. He was treated with aLH-RH agonist (Decapeptyl retard monthly). During 1998 his-alkalinephosphatase begun to raise from 132 up to 167 U/I (normal value <110U/I). Beginning in November 1998, he was treated orally twice daily with250 mg of sodium 4-phenylbutyrate according to the retard tablets ofExample 1. His PSA dropped to unmesurable levels and his alkalinephosphatase dropped gradually to 114 U/I on Dec. 14, 1999. He nevercomplained about bone pain. He died on Apr. 24, 2000, due to heartattack with congestive heart failure. The phenylbutyrate was welltolerated without side-effects.

1. A pharmaceutical unit dosage form comprising a therapeuticallyeffective amount of a 4-phenylbutyric acid salt, having prolongedrelease of the active ingredient and being suitable for alleviating andcuring various diseases of a human patient upon once or twice daily oraladministration to said patient.
 2. A pharmaceutical dosage formaccording to claim 1, characterised in that the 4-phenylbutyrate salt issodium 4-phenylbutyrate.
 3. A pharmaceutical dosage form according toclaim 1, characterised in that the prolonged release is achieved byhydroxypropylmethylcellulose with a molecular weight of 20,000-120,000.4. A pharmaceutical dosage form according to claim 1, characterised inthat it contains 250 mg of sodium 4-phenylbutyrate as active ingredient.5. A pharmaceutical dosage form according to claim 1, characterised inthat it contains—about 250 mg of sodium phenylbutyrate, about 146 mg ofhydroxypropylmethylcellulose type 2208 USP XXII of 100 or 4000 cps,about 261 mg of lactose, about 30 to 60 mg, in particular 31.25 mg, ofmicrocrystalline cellulose (Avicel® PH 102, Select chemie, orCellactose®, Meggle), about 10 mg of hardened vegetable oil, or e.g.talcum, about 1.5 mg of magnesium stearate, and optionally about 1 mg ofhighly dispersed silicon dioxide, so that cores prepared thereof weighabout 0.7 g.
 6. A pharmaceutical dosage form according to claim 1,characterised in that 24,000 of the cores are provided with a filmcoating produced from about 7,850 g of isopropylalcohol, about 3,360 gof Eudragit®L 12.5, about 66 g of dibutyl phthalat, about 18.0 g ofMiglyol® 812 and about 56 g of polyethylenglycol PEG
 400. 7. A processfor the preparation of a pharmaceutical dosage form according to claim1, characterised in that the dosage form is prepared in a conventionalmanner.
 8. The use of a pharmaceutical dosage form as set forth in claim1 for the treatment of benign prostate hyperplasy, cancer, leukemias,cystic fibrosis, AIDS, kidney and liver failures, thalassemia and ureacycle disorders comprising the twice-daily oral administration of atherapeutically effective dosage thereof to a patient.
 9. The use of apharmaceutical dosage form as set forth in claim 1 for the treatment ofcarcinoma, comprising the twice-daily oral administration of atherapeutically effective dosage thereof to a patient.